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Abstract

Human T-cell leukemia/lymphoma virus (HTLV-I) is the etiological agent of the lymphoproliferative disorder, adult T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease, tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). It is estimated that 20-30 million people worldwide are infected with HTLV-I, with 1-5% having a life-time risk of developing ATLL. HTLV is endemic in southwestern Japan, along with the Caribbean basin, Africa, South America, southwestern portions of North America, and Eastern Europe. ATLL develops over a long latency period of approximately 20 years, which is marked by the accumulation of genetic changes, such as constitutive activation of the IL-2 receptor signaling, JAK/STAT, NF-κB, AP-1, and inhibition of apoptotic pathways. In addition, long-term proliferation and maintenance of HTLV-I infected cells requires an increase in the cellular reverse transcriptase, telomerase. Telomerase extends the ends of chromosomal DNA by synthesizing repetitive tracts (TTAGGG) of DNA. These tandem arrays, termed telomeres, can protect from chromosomal loss, which occurs during each successive cellular division. In 90% of all cancer cells, telomerase is reactivated and allows the tumorgenic cell to sustain indefinite proliferation in absence of apoptosis and/or senescence. My work has specifically focused on the interaction of HTLV-I and telomerase, along with an examination of telomere lengths and biology in HTLV-I infected cells. The following studies demonstrate that telomerase expression and activity are greatly enhanced in HTLV-I infected cell lines and ATLL patient samples. Similar to other oncogenic viruses, we find that despite reactivation of telomerase activity, telomeres are shortened. However, these telomeres do not trigger cellular senescence and/or apoptosis, and are maintained at a shortened length, compared to normal cells, through increased telomerase expression, along with enhanced expression of telomere binding proteins (shelterin). Shelterin complexes protect against DNA repair mechanisms, control telomerase access to the telomere ends, and aid in determining the structure of telomeres. We have also performed a comprehensive investigation into telomerase regulation during HTLV-I infection and found, in addition to positive regulation by the transcription factors, c-Myc and Sp1, that IL-2R signaling leads to impairment in the telomerase inhibitor, WT1. IL-2R signaling promotes cytoplasmic retention of WT1, which normally binds to the hTERT promoter and negatively regulates telomerase expression. Finally, we demonstrate the importance of telomerase activity during HTLV-I infection, by showing that long-term inhibition of telomerase with the telomerase inhibitor, AZT, leads to telomere shortening and p53-mediated cellular senescence in tumor cells carrying a transcriptionally active p53. ATLL patients that carry a functional p53 are able to undergo complete or partial remission when treated with AZT, implying that AZT therapy may serve as a first line treatment option during ATLL disease.